Therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) are late complications of the successful use of cytotoxic therapy for the treatment of malignant diseases. The most common type presents after a latency of ~5 years in patients who received alkylating agents, and is characterized by loss or deletion of chromosomes 5 and/or 7. In contrast, patients who develop t-AML following treatment with drugs targeting topoisomerase II typically have recurring translocations, e.g., MLL gene at 11q23. t-MDS/t-AML represents an important model for cancer for several reasons. First, the incidence of this disorder is rising, as a result of the increasing number of cancer survivors. Second, the development of t-AML provides a unique opportunity to examine the effects of mutagens on carcinogenesis in humans, as well as the issue of genetic susceptibility and factors that predispose to the development of cancer. Survival times of t-AML patients are typically short, and new therapeutic approaches are needed. The goal of this program project is to elucidate the molecular mechanisms and genetic susceptibilities leading to t-MDS/t-AML. Dr. Onel (Project 1) will undertake genome-wide association studies of germline DNA from patients with t-AML to identify copy number alterations and genetic variants that may be genetic risk factors or biomarkers for t-AML. In complementary studies, Dr. Downing (Project 2) will undertake genome-wide studies to map copy number changes and somatic alterations associated with t-AML by analyzing leukemia cells, many of which are paired with samples studied in Projects 1, 3, and 4. Dr. Le Beau (Project 3) focuses on the identification and functional analysis of a myeloid leukemia tumor suppressor gene(s) (TSG) on 5q. In complementary studies, Dr. Shannon (Project 4) focuses on the identification and functional analysis of candidate TSGs on 7q. In addition, both projects emphasize the identification of secondary mutations that cooperate with myeloid leukemia suppressor genes on 5q or 7q. Each project utilizes the Patient Access, Data Management and Cell Storage Core (Core A), as well as the Administrative Core (Core B). Core A insures an orderly flow of leukemia and germline samples to the four projects, and the collection, and analysis of critical clinical, biological, and statistical data. Core B (Administrative Core) provides administrative and organizational support to the Program. The Program Project is integrated by its use of a common set of patients for molecular analysis with the goal of developing an improved understanding of the etiology of t-MDS/t-AML, the genetic pathways involved in the pathogenesis of t-MDS/t-AML, and genetic susceptibility to t-AML. These studies may lead, ultimately, to the development of individualized cancer prevention and early detection strategies, such as altered primary therapy.